A drug delivery system (DDS) has been increasingly used in therapeutic applications for various diseases as an ideal administration form of pharmaceutical agents. Especially, there has been widely investigated a development for improving blood circulation by modifying a pharmaceutical agent with polyethylene glycol, and there have been placed on the market pharmaceutical agents in which a cytokine such as interferon or GCSF is modified with polyethylene glycol. Heretofore, in polyethylene glycol derivatives, a type of derivatives having one reactive functional group at an end of polyethylene glycol is common but, in recent years, a multi-arm polyethylene glycol in which plural functional groups are introduced in one molecule has been used. Since the multi-arm polyethylene glycol has plural reactive points with a drug, there may be mentioned an advantage that a dose of the drug per unit weight can be increased. However, in the case where the polyethylene glycol derivative contains one having a different number of functional groups, there are contained those in which the number of the drugs modified with one molecule of polyethylene glycol is different, so that there arises a problem that the drug is not homogeneous as a pharmaceutical.
In addition, utilizing high water-solubility and biocompatibility of polyethylene glycol, there has been also advanced a development of water-swelling polyethylene glycol hydrogel in which polyethylene glycol and other molecule are combined. Various applications of the polyethylene glycol hydrogel has been investigated in biological and medical fields, for example, adhesive/hemostatic agents, adhesion prevention agents, carriers for drug controlled release, regenerative medical materials, and the like. Also as polyethylene glycol for the hydrogel uses, multi-arm type having more reactive points is useful for forming a crosslinked structure with the other molecule. Particularly, in the case where the hydrogel is used as a carrier for drug controlled release or a regenerative medical material, a quality of a narrower molecular weight distribution is desired for strictly controlling permeation and a diffusion rate of a drug or a protein as a growth factor of a cell from the gel.
As a raw material for the multi-arm polyethylene glycol, it is common to use a polyol corresponding to the desired number of functional groups. For example, ring-opening polymerization of ethylene oxide is conducted using glycerin or the like for three-arm one or pentaerythritol or the like for four-arm one as a raw material. Since these low-molecular-weight raw materials hardly contain impurities, it is possible to form polyethylene glycol of a high quality having a relatively narrow molecular weight distribution.
On the other hand, as six-arm and eight-arm polyethylene glycols, there have been known those using a polyglycerol such as tetraglycerin or hexaglycerin as a low-molecular-weight raw material. The polyglycerol is usually a mixture containing products having plural degrees of polymerization and/or isomers. Since it is difficult to purify the mixture into a single component owing to high polarity, a multi-arm polyethylene glycol of a low quality having a wide molecular weight distribution is formed when ethylene oxide is added thereto.
Against such a problem, there has been made an attempt to solve it by adding ethylene oxide using a low-molecular-weight compound having a high purity as a raw material. In Patent Document 1, six-arm and eight-arm polyethylene glycols have been synthesized using dipentaerythritol and tripentaerythritol as raw materials. Moreover, in Patent Document 2, a six-arm polyethylene glycol has been synthesized using sorbitol as a raw material.